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781.
Massively parallel screening of the receptorome 总被引:1,自引:0,他引:1
The National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (PDSP) is a resource that provides free screening of novel compounds to academic investigators. This program differs from other public-sector screening programs in that compounds are screened against a large panel of transmembrane receptors, channels, and transporters, a selection that currently includes a large portion of the whole neuro-receptorome. This review discusses the research areas that can profit from this resource, exemplified by recent findings. The first area is the identification of side effects of medications. Examples include the identification of the histamine H(1) receptor as being responsible for weight gain under antipsychotic treatment and the association of 5 HT(2B) receptor agonism with cardiac valvulopathy, which led to the removal of several medications. A second area is the identification of mechanisms of actions of medications and natural products. Examples are the finding that the kappa opioid receptor is the pharmacological target of the potent hallucinogen salvinorin A, that ephedrine and related compounds are not acting through direct sympathomimetic action, the identification of a strong dopaminergic action of WAY 100635, a compound that had been used as a selective 5 HT(1A) antagonist, and the discovery that the metabolite desmethylclozapine activates M(1) muscarinic receptors, an activity that might contribute to the clinical efficacy of the antipsychotic drug clozapine. A third, relatively new area is the identification of inert compounds as agonists for engineered designer receptors that no longer respond to their natural ligand (DREADDs) but exhibit unchanged signaling properties. 相似文献
782.
Mach T Chimerel C Fritz J Fertig N Winterhalter M Fütterer C 《Analytical and bioanalytical chemistry》2008,390(3):841-846
A microfluidic device was designed allowing the formation of a planar lipid bilayer across a micron-sized aperture in a glass
slide sandwiched between two polydimethylsiloxane channel systems. By flushing giant unilamellar vesicles through a 500-μm-wide
channel above the hole, we were able to form a planar lipid bilayer across the hole, resulting in a giga-seal. We demonstrate
incorporation of biological nanopores into the bilayer. This miniaturized system offers noise recordings comparable to open
headstage noise (under 1 pA RMS at 10 kHz), fast precision perfusion on each side of the membrane and the use of nanoliter
analyte volumes. This technique shows a promising potential for automation and parallelization of electrophysiological setups. 相似文献
783.
Phosphoric acid doped polybenzimidazole (PBI) membranes have been covalently cross‐linked with dichloromethyl phosphinic acid (DCMP). FT‐IR measurements showed new bands originating from bonds between the hydrogen bearing nitrogen in the imidazole group of PBI and the CH2 group in DCMP. The produced cross‐linked membranes show increased mechanical strength, making it possible to achieve higher phosphoric acid doping levels and therefore higher proton conductivity. Oxidative stability is significantly improved and thermal stability is sufficient in a temperature range of up to 250°C, i.e. within the temperature range of operation of PBI‐based fuel cells. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
784.
Velardez GF Lemke HT Breiby DW Nielsen MM Møller KB Henriksen NE 《The journal of physical chemistry. A》2008,112(35):8179-8187
The structures of the ground and excimer states of perylene pairs are calculated [using density functional theory (DFT) and time-dependent DFT techniques] in a free as well as a crystal environment, and their spectroscopic properties are studied for the most stable configurations. The vertical transition energies for the absorption and emission bands are obtained, and they are in good agreement with experimental data. In these calculations, up to six excited states are considered. With the calculated structures of the ground and excimer states, the scattering factors are analyzed as a function of the concentration of excimers in a crystal. The intensity of the 110, 005, and 0 10 0 reflections are found to be fairly sensitive to the presence of excimers in the crystal. The finite (nanosecond) lifetime of the excimer may make it possible to observe this state using time-resolved X-ray diffraction techniques. 相似文献
785.
Niels Grønbæk 《Proceedings Mathematical Sciences》2008,118(2):235-243
Let be a Banach algebra and let X be a Banach -bimodule. In studying (,X) it is often useful to extend a given derivation D: → X to a Banach algebra containing as an ideal, thereby exploiting (or establishing) hereditary properties. This is usually done using (bounded/unbounded) approximate
identities to obtain the extension as a limit of operators b ↦ D(ba) − b.D(a), a ε in an appropriate operator topology, the main point in the proof being to show that the limit map is in fact a derivation.
In this paper we make clear which part of this approach is analytic and which algebraic by presenting an algebraic scheme
that gives derivations in all situations at the cost of enlarging the module. We use our construction to give improvements
and shorter proofs of some results from the literature and to give a necessary and sufficient condition that biprojectivity
and biflatness is inherited to ideals. 相似文献
786.
Bak M Schultz R Vosegaard T Nielsen NC 《Journal of magnetic resonance (San Diego, Calif. : 1997)》2002,154(1):28-45
Software facilitating numerical simulation of solid-state NMR experiments on polypeptides is presented. The Tcl-controlled SIMMOL program reads in atomic coordinates in the PDB format from which it generates typical or user-defined parameters for the chemical shift, J coupling, quadrupolar coupling, and dipolar coupling tensors. The output is a spin system file for numerical simulations, e.g., using SIMPSON (Bak, Rasmussen, and Nielsen, J. Magn. Reson. 147, 296 (2000)), as well as a 3D visualization of the molecular structure, or selected parts of this, with user-controlled representation of relevant tensors, bonds, atoms, peptide planes, and coordinate systems. The combination of SIMPSON and SIMMOL allows straightforward simulation of the response of advanced solid-state NMR experiments on typical nuclear spin interactions present in polypeptides. Thus, SIMMOL may be considered a "sample changer" to the SIMPSON "computer spectrometer" and proves to be very useful for the design and optimization of pulse sequences for application on uniformly or extensively isotope-labeled peptides where multiple-spin interactions need to be considered. These aspects are demonstrated by optimization and simulation of novel DCP and C7 based 2D N(CO)CA, N(CA)CB, and N(CA)CX MAS correlation experiments for multiple-spin clusters in ubiquitin and by simulation of PISA wheels from PISEMA spectra of uniaxially oriented bacteriorhodopsin and rhodopsin under conditions of finite RF pulses and multiple spin interactions. 相似文献
787.
J Nygaard HK Munch PW Thulstrup NJ Christensen T Hoeg-Jensen KJ Jensen L Arleth 《Langmuir : the ACS journal of surfaces and colloids》2012,28(33):12159-12170
Precise control of the oligomeric state of proteins is of central importance for biological function and for the properties of biopharmaceutical drugs. Here, the self-assembly of 2,2'-bipyridine conjugated monomeric insulin analogues, induced through coordination to divalent metal ions, was studied. This protein drug system was designed to form non-native homo-oligomers through selective coordination of two divalent metal ions, Fe(II) and Zn(II), respectively. The insulin type chosen for this study is a variant designed for a reduced tendency toward native dimer formation at physiological concentrations. A small-angle X-ray scattering analysis of the bipyridine-modified insulin system confirmed an organization into a novel well-ordered structure based on insulin trimers, as induced by the addition of Fe(II). In contrast, unmodified monomeric insulin formed larger and more randomly structured assemblies upon addition of Fe(II). The addition of Zn(II), on the other hand, led to the formation of small quantities of insulin hexamers for both the bipyridine-modified and the unmodified monomeric insulin. Interestingly, the location of the bipyridine-modification significantly affects the tendency to hexamer formation as compared to the unmodified insulin. Our study shows how combining a structural study and chemical design can be used to obtain molecular understanding and control of the self-assembly of a protein drug. This knowledge may eventually be employed to develop an optimized in vivo drug release profile. 相似文献
788.
Dolman ME van Dorenmalen KM Pieters EH Sparidans RW Lacombe M Szokol B Orfi L Kéri G Bovenschen N Storm G Hennink WE Kok RJ 《Macromolecular bioscience》2012,12(1):93-103
The development of a macromolecular conjugate of a multitargeted tyrosine kinase inhibitor is described that can be used for renal‐specific delivery into proximal tubular cells. A novel sunitinib analogue, that is, 17864, is conjugated to a NH2‐PAMAM‐G3 dendrimer via the platinum (II)‐based Universal Linkage System (ULS?). The activity of 17864 is retained after coordination to the ULS linker alone or when coupled to NH2‐PAMAM‐G3. 17864‐UlS‐NH2‐PAMAM‐G3 is non‐toxic to proximal tubular cells in vitro. After intravenous administration to mice, 17864‐UlS‐NH2‐PAMAM‐G3 rapidly and efficiently accumulates in the kidneys. These results are encouraging for future studies focusing on the development of novel therapeutics for the treatment of renal diseases.
789.
Gonnelli G Hulstaert N Degroeve S Martens L 《Analytical and bioanalytical chemistry》2012,404(4):1069-1077
Proteomics research has taken up an increasingly important role in life sciences over the past few years. Due to a strong push from publishers and funders alike, the community has also started to freely share its data in earnest, making use of public repositories such as the highly popular PRIDE database at EMBL-EBI. Reuse of these publicly available data has so far been confined to rather specific, targeted reanalyses, but this limited reuse is set to expand dramatically as repositories continue to grow exponentially. Examples of large-scale reuse are readily found in other omics disciplines, where more comprehensive public data have already accumulated over longer periods. Here, a typical example of integrative data reuse is provided by the construction of so-called expression atlases. We here therefore investigate the issues involved in using the human data currently stored in the PRIDE database to construct a robust, tissue-specific protein expression atlas from tandem-MS based label-free quantification. 相似文献
790.
Møllendal H Margulès L Motiyenko RA Larsen NW Guillemin JC 《The journal of physical chemistry. A》2012,116(16):4047-4056
The rotational spectrum of cyanoacetaldehyde (NCCH(2)CHO) has been investigated in the 19.5-80.5 and 150-500 GHz spectral regions. It is found that cyanoacetaldehyde is strongly preferred over its tautomer cyanovinylalcohol (NCCH═CHOH) in the gas phase. The spectra of two rotameric forms of cyanoacetaldehyde produced by rotation about the central C-C bond have been assigned. The C-C-C-O dihedral angle has an unusual value of 151(3)° from the synperiplanar (0°) position in one of the conformers denoted I, while this dihedral angle is exactly synperiplanar in the second rotamer called II, which therefore has C(s) symmetry. Conformer I is found to be preferred over II by 2.9(8) kJ/mol from relative intensity measurements. A double minimum potential for rotation about the central C-C bond with a small barrier maximum at the exact antiperiplanar (180°) position leads to Coriolis perturbations in the rotational spectrum of conformer I. Selected transitions of I were fitted to a Hamiltonian allowing for this sort of interaction, and the separation between the two lowest vibrational states was determined to be 58794(14) MHz [1.96112(5) cm(-1)]. Attempts to include additional transitions in the fits using this Hamiltonian failed, and it is concluded that it lacks interaction terms to account satisfactorily for all the observed transitions. The situation was different for II. More than 2000 transitions were assigned and fitted to the usual Watson Hamiltonian, which allowed very accurate values to be determined not only for the rotational constants, but for many centrifugal distortion constants as well. Two vibrationally excited states were also assigned for this form. Theoretical calculations were performed at the B3LYP, MP2, and CCSD levels of theory using large basis sets to augment the experimental work. The predictions of these calculations turned out to be in good agreement with most experimental results. 相似文献